ABSTRACT Based on androgen-dependency for growth of prostate cancer, as well as normal prostate, anti-hormone therapy is typically initiated using selective androgen receptor modulators (SARMs). It is important to delineate new, unexpected aspects critical to AR actions, and new technologies to bear on the problem of prostate cancer. Although initially effective, resistance invariably fails as a tumor becomes androgen-independent or hormone refractory. In order to design new approaches to overcome resistance, it is necessary to understand the molecular basis of resistance. Although several models of resistance have been proposed, including mutations of the androgen receptor, these can account for only a very small percent of clinical resistance. Under the initial Grant cycle, we successfully defined a model for resistance based on macrophage:prostate cancer cell interactions which resulted in IL-1-MEKK1-TAB2-dependent derepression of AR target genes in the presence of SARMs, based on dismissal of the NCoR corepressor complex. The recruitment of TAB2 to serve as a molecular beacon for these events is specific to sex steroid receptors, reflective of evolutionarily conservation for key reproductive biological functions. However, we have also obtained data for unexpected components of a pathway that normally prevents ligand-dependent AR activation, providing new therapeutic possibilities. These unexpected mechanisms for hormone independence include failure of inhibitory histone methylation events and actions of a specific regulatory component of the NCoR complex. Our recent introduction of new technologies has revealed rapid AR-dependent changes in nuclear architecture provides an entirely new concept of androgen-dependent gene activation and new targets for preventing resistance. By developing and applying a novel genome-wide promoter location analysis method sufficiently sensitive to be suitable for use with clinical biopsy specimens, to issues of chromosomal interactions, coupled with powerful cell biological tools, we propose to delineate the molecular events underlying these additional mechanisms. Together, understanding these unexpected specific regulatory strategies should provide a series of leads for new therapeutic approaches to clinical resistance in prostate cancer. Relevance: Prostate cancer represents a major health problem in the United States and elsewhere, and is a source of major familiar and personal tragedy and societal expense. Our studies of androgen receptor and prostate cancer has direct relevance to our understanding and treatment of this disease, with implications for breast cancer as well.